Knowledge concerning the pharmacology, biochemical organization and regulation of mesotelencephalic dopaminergic (DA) neurons is crucial in facilitating the development of selective agents to alter function of these systems and for obtaining a better understanding of their role in normal and abnormal behavior. Antipsychotic drugs (APD) have one property in common, namely an ability to block DA receptors and influence the function of central DA neurons. Although the DA receptor blocking properties of APDs have been appreciated for a long time, it is still unclear whether this property is related to the therapeutic action of these drugs or which if any DA system is involved. Our studies will focus on the mesotelencephalic DA neurons with special attention directed at investigating the biochemical and pharmacological heterogeneity of these neurons and the role played by autoreceptors and afferent inputs in determining the physiological and pharmacological response of these neurons. In view of our experiments demonstrating that DA autoreceptors may regulate protein carboxylmethylation (PCM), we will investigate the possible role played by PCM in autoreceptor mediated modulation of DA synthesis and release and its role in Ca++ calmodulin regulation of tyrosine hydroxylase. The mesoprefrontal DA system, which has been demonstrated to have a number of unique properties and speculated to be a possible target site for the therapeutic actions of APD will receive major attention and be compared to the mesopiriform, mesolimbic and nigrostriatal systems. We have shown that this subset of mesocortical neurons lacks autoreceptors and consequently has a high physiological activity and rapid transmitter turnover. Following prolonged adminstrations of APD, the mesoprefrontal DA neurons, unlike other mesotelencephalic DA neurons, do not show biochemical tolerance or a state of depolarization inactivation. This system is very sensitive to stress and environmental perturbations and the activation produced can be prevented by benzodiazepine pretreatment, further suggesting a possible involvement in emotional behavior. Since our recent pilot studies have demonstrated that the mesoprefontal DA neurons are selectively activated by anxiogenic beta carbolines, we plan to characterize this effect and study the interaction with acute and chronic treatment with APD. In view of the potential application of these observations to clinical studies, we will determine if similar, selective effects are observed on mesocortical DA systems in non-human primates.